The cyclosporins are a family of, neutral, hydrophobic cyclic undecapeptides, containing a novel nine-carbon amino acid (MeBmt) at position 1 of the ring that exhibit potent immunosupressive, antiparasitic, fungicidal, and chronic anti-inflammatory properties. The naturally occuring members of this family of structurally related compounds are produced by various fungi imperfecti. Cyclosporins A and C, are the major components. Cyclosporin A, which is discussed further below, is a particularly important member of the cyclosporin family of compounds. Twenty four minor metabolites, also oligopeptides, have been identified: Lawen et al, J. Antibiotics 42, 1283 (1989); Traber et al, Helv. Chim. Acta 70, 13 (1987); Von Wartburg and Traber Prog. Med. Chem., 25, 1 (1988).
Isolation of cyclosporins A and C, as well as the structure of A were reported by A. Ruegger et al., Helv. Chim. Acta 59, 1075(1976); M. Dreyfuss et al., J. Appl. Microbiol. 3, 125 (1976). Crystal and molecular structures of the iodo derivative of A have been reported by T. J. Petcher et al., Helv. Chim. Acta 59, 1480 (1976). The Structure of C was reported by R. Traber et al., ibid. 60, 1247 (1977). Production of A and C has been reported by E. Harri et al., U.S. Pat. No. 4,117,118 (1978 to Sandoz). Isolation, characterization and antifungal activity of B, D, E, as well as the structures of A through D have been reported by R. Traber et al., Helv. Chim. Acta 60, 1568(1977). Isolation and structures of E, F, G, H, I: eidem, ibid. 65, 1655 (1982). Preparation of [2-Deutero-3-fluoro-D-Ala].sup.8 -CsA is disclosed by Patchett et al in GB 2,206,199A which was published on Dec. 29, 1988.
Further properties have also been reported in studies of the biological activity of A: J. F. Borel et al., Agents Actions 6, 468 (1976). Pharmacology: eidem, Immunology 32, 1017 (1977); R. Y. Calne, Clin. Exp. Immunol. 35, 1 (1979). Human studies: R. Y. Calne et al., Lancet 2, 1323(1978); R. L. Powles et al., ibid. 1327; R. L. Powles et al., ibid 1, 327 (1980). In vitro activity (porcine T -cells): D. J. White et al., Transplantation 27, 55 (1979). Effects on human lymphoid and myeloid cells: M. Y. Gordon, J. W. Singer, Nature 279, 433(1979). Clinical study of A in graft-versus-host disease: P. J. Tutschka et al., Blood 61, 318(1983).
As exemplified by the ever expanding list of indications for which Cyclosporin A has been found useful, the cyclosporin family of compounds find utility in the prevention of rejection of organ and bone marrow transplants; and in the treatment of psoriasis, and a number of autoimmune disorders such as type 1 diabetes mellitus, multiple sclerosis, autoimmune uveitis, and rheumatoid arthritis. Additional indications are discussed infra.
As is generally accepted by those of skill in the art, inhibition of secretion of interleukin-2 (IL-2) and other lymphokines from lymphocytes, is a useful indicator of intrinsic immunosuppressive activity of a cyclosporin analog. For a recent review of cyclosporin uses and mechanisms of action see Wenger et al Cyclosporine: Chemistry, Structure-Activity Relationships and Mode of Action, Progress in Clinical Biochemistry and Medicine, vol. 2, 176 (1986).
Cyclosporin A is a cyclic peptide which contains several N-methyl amino acids and, at position-8, contains a D-alanine. ##STR1## Abu=L-.alpha.-Aminobutyric acid Ala=L-Alanine
MeBmt=N-Methyl-(4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine PA1 Leu=L-Leucine PA1 MeLeu=N-Methyl-L-leucine PA1 MeVal=N-Methyl-L-valine PA1 Nva=L-Norvaline PA1 Sar=Sarcosine PA1 Thr=L-Threonine PA1 Val=L-Valine
Unless otherwise specified, each of the amino acids of the disclosed cyclosporin is of the L-configuration.
A generic structure, useful for describing cyclosprin A and analogs thereof is ##STR2## wherein the superscript number defines the position of the amino acid. Because of our specific interest in the amino acid at position 8, we will hereinafter replace "R.sup.8 " with "Y", thereby emphasizing that amino acid.
As is the practice in the field, a particular cyclosporin analog may be named using a shorthand notation identifying how the analog differs from cyclosporin A. Thus, cyclosporin C which differs from cyclosporin A by the threonine at position-2 may be identified as [Thr].sup.2 -cyclosporin or [Thr].sup.2 -CsA. Similarly, cyclosporin B is [Ala].sup.2 -CsA; cyclosporin D is [Val].sup.2 -CsA; cyclosporin E is [Val].sup.11 -CsA; cyclosporin F is [3-DesoxyMeBmt].sup.1 -CsA; cyclosporin G is [NVa].sup.2 -CsA; and cyclosporin H is [D-MeVal].sup.11 -CsA.
D-Serine and D-Threonine have been introduced into the 8-position of cyclosporin A by biosynthesis resulting in active compounds. See R. Traber et al. J. Antibiotics 42, 591 (1989). D-Chloroalanine has also been introduced into position-8 of Cyclosporin A by biosynthesis. See A. Lawen et al J. Antibiotics 42, 1283 (1989).
The present invention concerns new analogs of cyclosporin A and related cyclosporins for the care of immunoregulatory disorders and diseases, including the prevention, control and treatment thereof.